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Multidrug resistance protein 4 (MRP4) is a broadly expressed ATP-binding cassette transporter that is unique among the MRP subfamily for transporting prostanoids, a group of signaling molecules derived from unsaturated fatty acids. To better understand the basis of the substrate selectivity of MRP4, we used cryogenic-electron microscopy to determine six structures of nanodisc-reconstituted MRP4 at various stages throughout its transport cycle. Substrate-bound structures of MRP4 in complex with PGE1, PGE2 and the sulfonated-sterol DHEA-S reveal a common binding site that accommodates a diverse set of organic anions and suggest an allosteric mechanism for substrate-induced enhancement of MRP4 ATPase activity. Our structure of a catalytically compromised MRP4 mutant bound to ATP-Mg2+ is outward-occluded, a conformation previously unobserved in the MRP subfamily and consistent with an alternating-access transport mechanism. Our study provides insights into the endogenous function of this versatile efflux transporter and establishes a basis for MRP4-targeted drug design.

Aim: The induction of labor before due date has recently been proved to reduce the rate of cesarean sections and is not associated with increased risk of adverse perinatal outcomes as compared to expectant management. Controlled‐release dinoprostone (PGE2) vaginal insert has recently been approved for use in Japan. However, evidence regarding its efficacy in cervical ripening and labor induction before due date remains limited. We aimed to compare the efficacy of PGE2 vaginal inserts and mechanical dilation for labor induction before due date. Methods: This retrospective cohort study included 206 mothers at 37, 38, and 39 weeks' gestation delivered at our institution between January 2021 and October 2022. Perinatal outcomes, including the success rate of vaginal delivery, were compared between the PGE2 (n = 46) and metreurynter/laminaria tent (non‐PGE2) (n = 160) groups. The success rate of vaginal delivery was defined as the proportion of women who delivered vaginally within 48 h of initiating oxytocin augmentation. Results: The success rate of vaginal delivery was significantly higher in the PGE2 group (37/49, 80.4%) than in the non‐PGE2 group (106/177, 66.2%). Emergency cesarean section related to non‐reassuring fetal status was performed with none in the PGE2 group and with eight (5.0%) in the non‐PGE2 group. Conclusions: The rate of vaginal delivery was significantly higher in the PGE2 group for elective labor induction between 37 and 39 weeks. The PGE2 vaginal insert could increase the success rate of vaginal delivery for elective induction of labor at 39 weeks. [ABSTRACT FROM AUTHOR]

Objective: To explore the complications and pregnancy outcomes of vaginal dinoprostone vs. Cook's double balloon for the induction of labor among pregnancies complicated by small-for-gestational-age (SGA) at term. Methods: This retrospective study included consecutive singleton pregnancies complicated by SGA treated at Fujian Maternity and Child Health Hospital between January 2017 and December 2021. The patients were divided into the Cook's double balloon and dinoprostone groups according to the induction method they received. The primary outcome was vaginal delivery. Results: This study included 318 women [165 (aged 30.25 ± 4.72 years) and 153 (aged 28.80 ± 3.91 years) in the dinoprostone and Cook's balloon groups]. The dinoprostone group had a higher vaginal delivery rate than the Cook's balloon group (83.6% vs. 71.9%, p =.012). The cervical ripening duration (9.73 ± 4.82 vs. 17.50 ± 8.77 h, p <.001) and induction to delivery duration (22.11 ± 8.13 vs. 30.27 ± 12.28, p <.001) were significantly shorter in the dinoprostone group compared with the Cook's balloon group. Less women needed oxytocin infusion in the dinoprostone group compared with that in the Cook's balloon group (32.7% vs. 86.3%, p <.001). Dinoprostone was independently associated with vaginal delivery (HR = 1.756, 95%CI: 1.286–2.399, p =.000). The rates of uterine tachysystole and spontaneous rupture of the fetal membrane were significantly higher in the dinoprostone group than that in the Cook's balloon group (10.3% vs. 0.7%, p <.001; 7.3% vs. 1.3%, p =.012). There were no differences in maternal complications and neonatal outcomes between the two groups. Conclusion: In pregnant woman with pregnancies complicated by SGA, cervical ripening using dinoprostone were more likely to achieve vaginal delivery than those with Cook's balloon, and with a favorable complication profile. [ABSTRACT FROM AUTHOR]

Background: NSAID-induced gastropathy is a health burden that requires effective intervention. Among various prevention options, Gardenia jasminoides fruit extract (GJE) has demonstrated gastroprotective effects through anti-inflammatory pathways with a wide safety margin. However, the detailed molecular mechanisms of GJE regarding mucoprotective and anti-inflammatory effects remained to be explored. Therefore, we investigated the effects of GJE on NSAID-induced gastric injury in rats, focusing on the expression of the protective factors: prostaglandin E2 (PGE2) and mucin 5AC (MUC5AC), and the aggravating factors: inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB). Methods: Twenty-four male Sprague–Dawley rats were assigned to three experimental groups (n = 8/group): the control group, the NSAIDs group receiving indomethacin to induce gastric ulcers, and the NSAIDs with GJE pretreatment (NSAIDs + GJE) group. After a two-day experimental period, the stomachs were collected for histopathological examination, immunohistochemical staining, and protein expression analysis in gastric tissue lysates. Results: The NSAIDs group exhibited severe neutrophil infiltration with ulcers upon gastric histopathological examination. Pretreatment with GJE attenuated NSAID-induced gastropathy, as evidenced by reduced neutrophil infiltration and decreased ulceration. Immunohistochemical staining and Western blotting demonstrated reduced expressions of PGE2 and MUC5AC, while the expressions of iNOS and NF-κB were increased following NSAID administration. In comparison to the NSAIDs group, the NSAIDs + GJE group exhibited higher expressions of PGE2 and MUC5AC and lower expressions of iNOS and NF-κB, providing evidence of the gastroprotective effects of GJE. Conclusions: Pretreatment with GJE alleviated NSAID-induced gastric ulcers by increasing the expression of PGE2 and MUC5AC and decreasing the expression of iNOS and NF-κB. This study contributes to the understanding of the mechanisms by which GJE attenuates NSAID-induced gastropathy. Further studies are required to validate the effect of GJE in clinical settings. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Materials and Methods Results Conclusion To analyse whether some selected inflammatory biomarkers collected from venous blood and gingival crevicular fluid (GCF) were associated with the outcome of non‐surgical periodontal therapy.Two‐hundred and nine patients affected by periodontitis were enrolled in the study, who had undergone steps I and II therapy as well as a non‐surgical re‐instrumentation (NSRI) of periodontal pockets after 6 months. Serum (SE), plasma (PL) and GCF samples were quantitatively analysed for the following inflammatory biomarkers: active matrix metalloproteinase‐8 (aMMP‐8), prostaglandin E2 (PGE2) and surfactant protein D (SP‐D). Therapy outcomes were evaluated using a ‘treat‐to‐target’ endpoint (T2T) at the patient level, defined as ≤ 4 sites with pocket depth ≥ 5 mm.Patients presented with 23 ± 6 teeth (mean ± SD) at baseline. After steps I and II therapy, 41.6% of the patients reached T2T and after NSRI 47.4%. Univariate analysis identified a potential association between high levels of PL‐SP‐D and more favourable treatment outcomes. Multivariate binary logistic regression adjusted for sex, mean baseline probing depth, diabetes and current smoking status confirmed an independent relationship between baseline PL‐SP‐D and the T2T after steps I and II therapy (aOR 0.432, p = 0.011), implying that a higher level PL‐SP‐D at baseline is associated with a > 50% reduced risk of failing T2T. However, no such association was found for PL‐SP‐D and NSRI.Higher baseline PL‐SP‐D levels might be associated with more favourable treatment outcomes after steps I and II therapy. This may be due to its role in the regulation of neutrophil function. However, further investigation is required to confirm this hypothesis. If proven, PL‐SP‐D could play a role as a biomarker for identifying individuals who respond differentially to primary therapy. [ABSTRACT FROM AUTHOR]

Objective Materials and Methods Results Conclusion This retrospective study aimed to compare the outcomes of dinoprostone vaginal insert (PROPESS) and double balloon cook catheter (DBC) in term nulliparous pregnancies.A total of 1682 cases were enrolled, all of which were divided into two groups: PROPESS and DBC. The primary outcomes were rate of vaginal delivery (VD) and cesarean section (CS) and successful VD within 24 h and CS indications; the secondary outcomes were labor duration, oxytocin augmentation, complications during labor, maternal/neonatal outcomes, and predictors of successful VD within 24 h.There was no statistical difference in the rates of VD between the PROPESS group (73.74%) and the DBC group (77.73%) (p = 0.36). The VD rate within 24 h was significantly higher in PROPESS group than in the DBC group (55.45% vs. 38.43%, p < 0.001). The occurrence of nonreassuring fetal heart rate (NRFHR) patterns was higher in the CS indications of the PROPESS group than in the DBC group (56.86% vs. 37.81%, p < 0.001). The oxytocin augmentation was significantly lower in the PROPESS group than in the DBC group (52.79% vs. 94.9%, p < 0.001). The incidence of chorioamnionitis was significantly higher in the DBC group as compared with PROPESS group (4.36% vs. 1.34%, p < 0.001), while neonatal outcomes were comparable between the two groups. PROPESS (p < 0.001, odds ratio [OR] 2.478, 95% confidence interval [CI] 1.718–3.574), oxytocin augmentation (p < 0.001, OR 32.759, 95% CI 20.654–51.958), and amniotomy (p = 0.016, OR 1.897, 95% CI 1.331–2.704) were predictors of VD within 24 h.The effectiveness of delivery was comparable between the two groups. The PROPESS group resulted in a high successful VD rate within 24 h, although accompanied by NRFHR occurrence. Two cases with fetal presentation change (cephalic to breech) and four cases with umbilical cord prolapse were observed in the DBC group. PROPESS, oxytocin augmentation, and amniotomy were associated with VD interval within 24 h. [ABSTRACT FROM AUTHOR]

Predicting the success of vaginal delivery is an important issue in preventing adverse maternal and neonatal outcomes. This study sought to examine whether measurement of the angle of progression (AoP) can predict a successful vaginal delivery following induction of labour (IoL) among late term nulliparous women with a low (4>) Bishop score. This prospective study included consecutive nulliparous pregnant women whose gestational age was 41 weeks and 1–6 days (late-term). The AoP was measured at least three times and their means were calculated. During the study period, data of 150 women were included in the final analysis. Thirty-eight women underwent CS due to failure to progress (n=30) or NRGHR (n=8), while the remaining 112 women underwent NVD, with four women requiring vacuum extraction. The two groups were similar with respect to age, gestational age, BMI, estimated foetal weight, and birth weight. Women undergoing NVD differed significantly from those undergoing CS with respect to a greater ultrasonographic AoP (113.8±11.9° vs. 98.1±10.9°, p=0.0001), a shorter duration of dinoprostone use, shorter time to labour contraction, and a shorter duration of labour. In ROC analysis, the cut-off value for AoP was 100° for the prediction of successful IoL for NVD, with a sensitivity of 96 % and a specificity of 63 %. AoP may be a useful sonographic parameter for predicting successful vaginal delivery among nulliparous women at late term undergoing IoL; an AOP wider than 100° is associated with a high rate of vaginal delivery. [ABSTRACT FROM AUTHOR]

Introduction: Labor induction exhibits considerable variations in protocols and medication regimens. Limited studies compare vaginal dinoprostone inserts with different oral misoprostol dosages, considering parity influence. This study explores the distinctions among 10 mg vaginal dinoprostone inserts and oral misoprostol 25 μg every 2 and every 4 h for labor induction, stratified by parity. Material and Methods: This retrospective cohort study involved 607 participants across two hospitals. The primary outcome, time from induction to delivery, and secondary outcomes, including mode of delivery and maternal and fetal safety, were assessed. Results: Patient characteristics revealed differences in indication for labor induction, with the dinoprostone cohort having fewer post‐term and premature rupture of membranes cases but more intrauterine growth restriction/small‐for‐gestational age. Both oral misoprostol regimens showed a shorter time to delivery interval compared to the dinoprostone cohort (median: 1380 min [IQR 1381.0] and 1127.0 min [IQR 1214.0] vs 1631.5 [IQR 1736.2], p < 0.001 and p = 0.014). Only the difference between oral misoprostol q2h and vaginal dinoprostone remained significant for nulliparous but not multiparous women, losing significance over all the population after adjusting for confounding factors. The proportion of women giving birth within 24 h did not significantly differ between misoprostol q2h and dinoprostone after adjusting for confounders. When comparing misoprostol q4h with dinoprostone after confounder adjustment, an increased time to delivery interval for misoprostol q4h was found (p = 0.001). Both oral misoprostol regimens exhibited fewer meconium‐stained liquor (miso q4h: OR 0.44, miso q2h: OR 0.34) and cesarean sections (miso q4h: OR 0.48, miso q2h: OR 0.53) compared to dinoprostone, even after adjustment for confounders. Conclusions: Our study suggests that oral misoprostol 25 μg q4h is less effective than 10 mg vaginal dinoprostone for labor induction if parity and indication for induction are adjusted for, particularly in multiparous women. In terms of side effects, oral misoprostol regimens seem superior to vaginal dinoprostone. Our data support the individualized use of different agents for labor induction according to parity, indication for induction, bishop score, and women's preference. [ABSTRACT FROM AUTHOR]

• Limited evidence on best strategy with unfavorable cervix 24 h after first vaginal dinoprostone. • Efficacy, maternal and neonatal morbidity after repeated methods questioned. • Similar vaginal delivery and neonatal morbidity between vaginal dinoprostone and cervical ripening balloon. • Cervical ripening balloon more efficient with more favourable cervix or labor within 24 h. To compare dinoprostone vaginal insert (PG) with cervical ripening balloon (CRB) as second line of cervical ripening in women at term with a persistent unfavorable cervix after first PG. This retrospective cohort study comprised all women with singleton fetus in cephalic presentation who required cervical ripening at term (≥37 weeks) for maternal and/or fetal disease using repeated PG or CRB for a persistent unfavorable cervix (Bishop score <6) 24 h after first PG. Primary outcome was vaginal delivery rate. Secondary outcomes were favorable cervix (Bishop score ≥6) or labor within 24 h after second device placement, postpartum hemorrhage (PPH) and neonatal morbidity. 180 women were analyzed (127 repeated PG (70.6 %) and 53 CRB after first PG (29.4 %)). After second device, 93.3 % of women had a favorable cervix (Bishop score ≥6) or were in labor within 24 h, and the rate was significantly higher after CRB, compared to repeated PG (98.1 % vs. 91.3 %; p = 0.048). Vaginal deliveries were similar between groups (62.2 % after repeated PG vs. 54.7 % after CRB; p = 0.36). PPH was observed in 22.2 % of included women, and no difference was observed between groups (21.3 % vs. 21.4 %; p = 0.63). Neonatal morbidity was similar between groups (13.4 % vs. 9.4 %; p = 0.48). Vaginal delivery rate and neonatal morbidity were similar when using PG or CRB as second line in women at term with a persistent unfavorable cervix after first PG. CRB seemed to be more efficient on the cervix status, compared to repeated PG, in these women. [ABSTRACT FROM AUTHOR]

Background/Aim: As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled (52Mn) randomly methylated beta-cyclodextrin ([52Mn]Mn-DOTA-GA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [68Ga]Ga-DOTANAPamide and PGE2 selective [68Ga]Ga-DOTA-GA-RAMEB cyclodextrin. Materials and Methods: Post-injection of [68Ga]Ga-DOTA-NAPamide, [68Ga]Ga-DOTAGA-RAMEB, and [52Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter. Results: Although all tracers performed well in tumor identification, the highest standardized uptake values were detected in the [68Ga]Ga-DOTA-NAPamide scans. Corresponding to the ex vivo data, meaningful [52Mn]Mn-DOTAGA-RAMEB accumulation 1 h post-injection confirmed the tumor-targeting potential of the tracer. Temporal changes in PGE2/EP2 expression of the neoplasms may explain the significant differences observed between the tumor uptake of the two cyclodextrin probes and that of the 52Mn-labelled compound measured 1 h, 4 h, and 3 days post-injection (p≤0.01, p≤0.05). Conclusion: Although further pharmacokinetical optimization may be required, 52Mn-labelled cyclodextrin holds potential in melanoma diagnostics and the PET-based longitudinal assessment of tumor-associated PGE2/EP2 expression. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Methods Results Conclusion To compare and evaluate the differences between EGCG and phosphatidylcholine‐encapsulated EGCG in terms of their anti‐inflammatory and antioxidant capacities.In this study, transdermal absorption experiments were conducted to compare the absorption capacity of EGCG and phosphatidylcholine‐encapsulated EGCG. Subsequently, the disparity in anti‐inflammatory and antioxidant efficacy between EGCG and phosphatidylcholine‐encapsulated EGCG were evaluated through cytotoxicity experiments, as well as the determination of cellular inflammatory factors and the measurement of ROS content under different treatment conditions.The concentration of EGCG, encapsulated in phosphatidylcholine, in porcine skin is 40.76 ± 1.29 μg/cm2, which is significantly higher than the concentration of EGCG alone (31.62 ± 2.01 μg/cm2). Also, the ability of phosphatidylcholine‐encapsulated EGCG to suppress inflammatory factors such as tumor necrosis factor‐α (TNF‐α), cyclooxygenase‐2 (COX‐2), and prostaglandin E2 (PGE2) was notably superior to that of EGCG alone. Both phosphatidylcholine‐encapsulated EGCG and EGCG showed excellent ROS scavenging ability in terms of antioxidant capacity.The percutaneous absorption and anti‐inflammatory impact of EGCG encapsulated within phosphatidylcholine were substantially enhanced when compared to EGCG by itself. Additionally, both formulations exhibited enhanced ROS scavenging capacities, albeit the variance between them was not pronounced. These insights furnish a vital theoretical underpinning for the utilization of phosphatidylcholine‐encapsulated EGCG in cosmetic applications, specifically for fostering products with anti‐inflammatory and antioxidant benefits. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion To assess adverse obstetric and neonatal outcomes associated with the use of dinoprostone for induction of labor, with particular attention on categories for which caution is recommended by the Italian Medicines Agency and the European Medicine Agency.A retrospective multicenter observational study was conducted on a population of 1687 patients undergoing induction of labor with vaginal dinoprostone (gel or insert) between August 2019 and June 2022. Patients were subdivided based on maternal age, gestational age, and obstetric disorders. Data regarding the mode of delivery, the incidence of tachysystole, and the obstetric and perinatal outcomes were collected.The main adverse event associated with the use of dinoprostone was tachysystole. However, tachysystole was not associated with an increased risk of cesarean section (CS), neonatal intensive care (NICU) admission, low 1‐min Apgar, or umbilical cord acidosis. Maternal age greater than 35 years, gestational age greater than 40 weeks, and obstetric disorders were not associated with an increased rate of tachysystole, NICU admission, low 1‐ and 5‐min Apgar scores, and cord acidosis. The only associated adverse outcomes in those categories were postpartum hemorrhage with age greater than 35 years and tachysystole with gestational diabetes mellitus and hypertensive disorders. Not a single case of severe outcome (disseminated intravascular coagulation, uterine rupture, maternal and fetal death) was reported in the cohort.Providing there is adequate maternal and fetal surveillance, in an inpatient setting, dinoprostone could be safely administered for the induction of labor and considered appropriate in high‐risk pregnancies. Tachysystole can be self‐identified by the patient and effectively managed. [ABSTRACT FROM AUTHOR]

Novel benzophenone–thiazole hybrids with different substituents were synthesized and evaluated for anti‐inflammatory activity using an ex vivo human whole‐blood assay. All hybrids (3c and 5a–h) showed significant anti‐inflammatory activity via prostaglandin E2 (PGE2) release inhibition. Moreover, 5c (82.8% of PGE2 inhibition), 5e (83.1% of PGE2 inhibition), and 5h (82.1% of PGE2 inhibition) were comparable to the reference drugs. Molecular docking revealed potential preferable binding to the active sites of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase‐1 (mPGES‐1) enzymes. This study provides the first evidence that benzophenone–thiazole hybrids may also dock in mPGES‐1, a new attractive anti‐inflammatory drug target, besides providing promising ex vivo anti‐inflammatory activity. Thus, the novel hybrids are promising anti‐inflammatory lead compounds and highlight the significance of optimal substituent selection in the design of potent PGE2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that nuclear factor (NF)-κB is involved in the pathophysiology of mood disorders. Objectives and Methods: We conducted two experimental protocols in rats to investigate the effects of a selective NF-κB inhibitor (JSH-23) on (i) lipopolysaccharide (LPS)-induced inflammation and (ii) on behavioral phenotypes in rat models of depression (sucrose consumption test and forced swim test) and mania (amphetamine-induced hyperactivity test). Additionally, we tested the effects of JSH-23 on levels of inflammatory components (interleukin-6, prostaglandin E2, nuclear phospho-p65, and tumor necrosis factor-α) in the brain. Results: Acute treatment with JSH-23 (10 mg/kg, intraperitoneally [ip]) led to potent anti-inflammatory effects in LPS-treated rats, including a diminished hypothermic response to LPS and a reduction in pro-inflammatory mediators' levels in the brain. Chronic treatment with JSH-23 (3 mg/kg, ip, once daily, for 14 days) resulted in robust antidepressant-like effects (increased sucrose consumption and decreased immobility time). The antidepressant-like effects of JSH-23 were mostly accompanied by a reduction in levels of pro-inflammatory mediators in the brain. On the other hand, JSH-23 did not reduce amphetamine-induced hyperactivity. Conclusions: Altogether, these data suggest that NF-κB may be a potential therapeutic target for pharmacological interventions for depression. [ABSTRACT FROM AUTHOR]

To compare effectiveness and safety of the Cook's balloon with vaginal dinoprostone to induce labor in patients with previous cesarean section. Observational, and retrospective study that included pregnant women at ≥ 37 weeks' gestation, with unfavorable cervix, singleton pregnancy, intact membranes, and a previous cesarean section, who had undergone labor induction in the period 2014–2019. 170 patients (86 balloon-84 dinoprostone) were analyzed. The proportion of women achieving vaginal delivery within 24 h was higher in the dinoprostone than in double-balloon group (RR, 3.24; 95% CI, 1.36–7.72). No significant differences were detected in the first 48 h in vaginal deliveries (P =.749) or in cesarean section rates (P =.634). Nor were there differences in maternal or fetal safety profiles. A body mass index > 35 increased the risk of cesarean section by 1.53 times (P =.017) and a Bishop's test score < 3 by 1.91 times (P =.009). A vaginal delivery following a cesarean section decreased the probability of another cesarean section by 0.46 times (P =.039). Labor induction with vaginal dinoprostone achieves better vaginal delivery rates in the first 24 h vs Cook's balloon. While the difference in uterine rupture rate did not reach significance, this was higher in women receiving prostaglandin. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to evaluate low‐dose oral misoprostol induction, and compare different methods used in second‐line induction in patients with a Bishop score less than 6. Methods: This retrospective study analyzed the medical history and courses of pregnancy of all patients induced with first‐line of low‐dose oral misoprostol (50 μg every 4 h with a total of 200 μg/24 h) from April 2021 to June 2022 in a university hospital center, and reported outcomes according to the second‐line method of induction. Results: Among 437 labor inductions with low‐dose oral misoprostol, 120 patients required a second‐line induction. Predictive factors of first‐line failure were higher body mass index (P = 0.011), absence of premature rupture of membranes (P = 0.021) and earlier term of pregnancy (P < 0.001). Regarding second methods of induction of labor, time from induction to delivery was shorter in the oxytocin group than the dinoprostone and misoprostol groups (24.0 vs. 41 and 51.0 h, respectively; P < 0.001), and was also significantly shorter in the dinoprostone than the misoprostol group (P = 0.048). Cesarean section rates did not differ between the three groups (P = 0.651). There were no clinically significant differences in adverse events between the groups. Conclusion: Normal body mass index, previous rupture of membranes and later term of induction of labor were the three favoring success factors during first‐line oral misoprostol. In cases of a Bishop score <6, oxytocin may be the best option to reduce duration to delivery, with the same maternal‐fetal outcomes, including a similar rate of vaginal delivery. Synopsis: If a Bishop score was <6 after 24 h oral misoprostol, oxytocin could be the best method to reduce duration to delivery. [ABSTRACT FROM AUTHOR]

Context Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. Objective To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2, and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. Design Prospective population-based cohort study (Rotterdam Study). Setting General population. Participants 2178 participants (65% female, age 64 ± 8 years) Intervention(s) None. Main Outcome Measure(s) Serum sodium levels. Results Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each 2-fold higher PGE2 −0.19 mmol/L [95% confidence interval (CI) −0.31 to −0.06], PGEM −0.29 mmol/L (95% CI −0.41 to −0.17). This association was stronger in thiazide users (per 2-fold higher PGE2 −0.73 vs −0.12 mmol/L and PGEM −0.6 vs −0.25 mmol/L, P for interaction <.05 for both). A propensity score matching analysis of thiazide vs non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. Conclusion Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion, and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia specifically. [ABSTRACT FROM AUTHOR]

The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

Abstract Background The rates of labor induction and cesarean delivery is rising worldwide. With the confluence of these trends, the labor induction rate in trials of labor after cesarean can be as high as 27-32.7%. Induction of labor after one previous cesarean (IOLAC) is a high-risk procedure mainly due to the higher risk of uterine rupture. Nevertheless, the American College of Obstetricians and Gynecologists considers IOLAC as an option in motivated and informed women in the appropriate care setting. We sought to identify predictors of a composite of maternal and newborn adverse outcomes following IOLAC. Methods The electronic medical records of women who delivered between January 2018 to September 2022 in a Malaysian university hospital were screened to identify cases of IOLAC. A case is classified as a composite adverse outcome if at least one of these 11 adverse outcomes of delivery blood loss ≥ 1000 ml, uterine scar complications, cord prolapse or presentation, placenta abruption, maternal fever (≥ 38 0C), chorioamnionitis, intensive care unit (ICU) admission, Apgar score

Introduction. The physiological process by which the fetus and placenta are delivered from the uterus and pass through the vaginal canal for delivery is known as labor. Induction of labor involves deliberately initiating labor before it occurs naturally, using medical interventions or techniques to stimulate contractions and initiate the birthing process. Aim. This study aimed to investigate the factors that influence the success of labor induction procedures in Riyadh, Saudi Arabia, from January to April 2023. Subject and Methods. This retrospective chart review was conducted at the National Guard Hospital in Riyadh, Saudi Arabia. Data were collected from the patient chart of those who underwent labor induction from January to April 2023. The collected data were tabulated and cleaned in MS Excel. Final data were transferred to SPSS for subsequent data analysis. Results. Five hundred and thirty‐one pregnant women were analyzed. 52.7% were aged 30 years or below. The most common indication of IOL was post‐dated pregnancy (26.2%). 62% were normal deliveries, indicative of IOL success, while 31.1% were cesarean deliveries, indicative of IOL failure. In univariate analysis, women with lower gravidity (≤3) and who had received Propess were associated with cesarean delivery. In a multivariate regression analysis, women who received Prostin and increased parity were identified as the significant independent predictors of IOL success. Conclusion. IOL's success was dependent primarily on increasing parity and Prostin administration. However, lower gravidity (≤3) and Propess medication could lead to operative procedures among pregnant women. Hence, it is necessary to carefully assess the condition of pregnant women before directing them to IOL. [ABSTRACT FROM AUTHOR]

ABSTRACT Uterine vascular alterations take place in pyometra bitches speculatively influenced by prostaglandin and nitric oxide pathways. However, no causative effect of nitric oxide on endometrial vascularization was proved elsewhere for medically treated pyometra bitches. This study aimed to identify the main in situ uterine artery vasodilation pathway in pyometra bitches medically treated with antigestagen solely or coupled with prostaglandin. Pyometra bitches were enrolled into groups: Ovariohysterectomy at diagnosis (Control‐OHE; n = 7), Antigestagen (10 mg/kg aglepristone on Days 1, 2, and 8 after diagnosis; n = 5), and Antigestagen + luteolytic (aglepristone plus 1 μg/kg of cloprostenol from Days 1–7; n = 5). Treated bitches were ovariohysterectomized after 8 days of treatment. Uterine artery fragments from all bitches were collected for tissue nitric oxide and prostaglandin E2 assays. Control‐OHE group had lower uterine artery concentration of nitric oxide compared to treated bitches (Antigestagen and Antigestagen + luteolytic groups). No significant difference was verified between the medical treated groups. Uterine artery concentration of prostaglandin E2 was not different between control and treated bitches, as well as between both treated groups. In conclusion, nitric oxide and prostaglandin E2 are not directly involved in vascular modulation of the uterine artery, albeit pyometra medical treatment influences nitric oxide concentration in the uterine artery. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is one of the most prevalent malignancies affecting males; however, the role of inflammatory activity in the pathogenesis of this disease is not yet fully elucidated. Although inflammation is recognized as being closely associated with the onset and progression of PCa, the specific causal relationships between individual inflammatory factors and the disease require further clarification. Methods: Mendelian randomization (MR) methodologies can mitigate bias by utilizing whole-genome sequencing data, leveraging specific genetic variants to assess causal relationships between a given exposure and an outcome of interest. This research employed an MR approach to investigate the association between inflammatory cytokines and PCa. Results: In total, 44 inflammatory cytokines were evaluated in a large GWAS dataset to enable the drawing of robust conclusions. Elevated circulating Creactive protein (CRP) and prostaglandin E2 (PGE-2) levels were related to greater PCa risk. The reverse Mendelian randomization (MR) study indicates a causal relationship between prostate cancer and stem cell factor (SCF) (P=0.025). Conclusion: CRP and PGE-2 play crucial roles in the regulation of PCa development. Moreover, PCa may have an impact on SCF levels. Further research is imperative to elucidate whether these biomarkers can be effectively utilized to prevent or treat PCa. [ABSTRACT FROM AUTHOR]

Background: This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells. Results: Trp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1. Conclusions: The regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus. [ABSTRACT FROM AUTHOR]

Background: Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence. Methods: The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure. Results: The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity. Conclusion: Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential. Fecal SN-38 content as a surrogate predictor for SN-38 intestinal tissue exposure and irinotecan-induced severe delayed-onset diarrhea The intestinal SN-38 exposure, involving both the distribution of SN-38 from the blood vessel and the reabsorption of SN-38 from intestinal lumen, was shown to be closely related to irinotecan-induced diarrhea. However, intestinal SN-38 exposure is hard to measure in humans. Fecal SN-38 content could serve as a surrogate predictor of intestinal SN-38 exposure, which is dependent on biliary excretion, intestinal excretion to intestinal lumen and bacteria β-glucuronidase activities that convert SN-38G to SN-38. [ABSTRACT FROM AUTHOR]

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2‐agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2‐related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways. [ABSTRACT FROM AUTHOR]

There is controversial evidence that acidification of vaginal pH may increase the efficacy of vaginal prostaglandins in labor induction, with research being mainly focused on misoprostol. This study aims to evaluate the impact of this intervention on the progress of labor induction with dinoprostone (PGE2) vaginal tablet. This double-blind, parallel-group, randomized study was conducted between October 2021 and December 2022 at Alexandra General Hospital, Athens, Greece. A total of 230 women with singleton, full term pregnancy that were scheduled for labor induction were randomly divided into two groups: Group A, who received acidic vaginal wash (5 % acetic acid) and Group B, who received a normal saline vaginal wash. Afterwards, participants received a vaginal tablet of 3 mg dinoprostone every 6 h (maximum two doses). There were no statistically significant differences in mode of delivery, duration of different labor stages, Bishop score changes and possible complications. Participants in the acidification group needed less often labor augmentation with oxytocin and epidural anesthesia (p=0.03). Vaginal acidification seems to have no effect on the efficacy of the dinoprostone vaginal tablet. Even though it may reduce the need for oxytocin augmentation, there is no apparent benefit on clinical outcomes, such as reduction in cesarean section rates or shorter labor duration. Future research is necessary in order to validate these findings. [ABSTRACT FROM AUTHOR]

Objective: To evaluate vaginal delivery in obese women who underwent cervical ripening at term using a dinoprostone vaginal insert or a cervical ripening balloon (CRB), and to assess maternal and neonatal morbidity according to the method. Methods: A prospective cohort study including obese women with a live singleton fetus in cephalic presentation who required cervical ripening at term (≥37 weeks) for maternal and/or fetal disease using a dinoprostone vaginal insert or a CRB. The primary outcome was vaginal delivery. Secondary outcomes were a favorable cervix (Bishop score >6) after 24 h, the time from device insertion to delivery, and composite maternal and neonatal morbidity. Results: In total, 135 consecutive women were analyzed (107 CRB, 79.3%; 28 dinoprostone vaginal insert, 20.7%). Vaginal delivery (86 [80.4%] after CRB vs 19 [67.9%] after dinoprostone vaginal insert; P = 0.248), favorable cervix within 24 h after device placement (52 [48.6%] vs 17 [60.7%]; P = 0.264), and maternal morbidity (12 [11.2%] vs 4 [14.3%]; P = 0.646) were similar between the groups. The time from device insertion to delivery also did not differ between the groups. Neonatal morbidity was significantly higher after the dinoprostone vaginal insert (11 [39.3%] vs 20 [18.7%]; P = 0.030). Cervical ripening using the dinoprostone vaginal insert, compared with the CRB, was significantly associated with neonatal morbidity (adjusted odds ratio 4.00, 95% confidence interval 1.34–12.5), but not with maternal morbidity (adjusted odds ratio 1.23, 95% confidence interval 0.30–4.38). Conclusions: Vaginal delivery, a favorable cervix after 24 h, the time from device insertion to delivery, and maternal morbidity did not significantly differ between the CRB and the dinoprostone vaginal insert for cervical ripening in obese women at term. Nevertheless, neonatal morbidity was significantly associated with the dinoprostone vaginal insert, compared with the CRB, among obese women who required cervical ripening at term. Synopsis: Neonatal morbidity was associated with vaginal dinoprostone, compared with a CRB, among obese women at term, without a difference in vaginal delivery and maternal morbidity. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) has been reported to be involved in reproduction as one of the most abundant and widely distributed prostaglandins in invertebrates. Regulating gonad development and gamete production in mollusks can greatly assist artificial breeding, which is believed to promote the commercial benefits of various mollusk species. In the present study, the contents of PGE2 in the gonads of abalone at different developmental stages (maturing stage, ripe stage, and spawning stage) and reproduction states (before and after spawning) were measured. A higher PGE2 level was found in the gonads of abalones at the ripe stage than other stages, and the highest PGE2 level was detected in the ovaries of female H. diversicolor in the UV-stimulated group. Then the effects of PGE2 injection on the spawning efficiency were explored, and the gamete emission rates of female and male abalone were significantly increased after PGE2 injection. Through qRT-PCR and in situ hybridization assay, higher expression levels and wide distribution of phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), prostaglandin E synthases (PGES2), and prostaglandin E2 receptor 4 (EP4) in the gonads of H. diversicolor were observed after spawning. It is speculated that PGE2 may promote the reproductive cycle in both male and female H. diversicolor, although the regulation mechanism of PGE2 in female and male abalone might be different. The results will be useful for the application of PGE2 in the abalone aquaculture practices to increase the reproduction efficiency in future. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is a chronic multifactorial disease caused by microorganisms such as G-anaerobes in the periodontal tissues. It activates host defense cells and releases inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE2). Ganoderma lucidum is a traditional medicinal mushroom with anti-inflammatory effects against various diseases. Biologically, different levels of its active constituents, such as triterpenoids and phenolic compounds, reduce inflammation with various pathways. Furthermore, the constituents inhibit toll-like receptor 4, MyD88 receptors, and the activities of nuclear factor-kappa B, which synthesize TNF-α and PGE2. Purpose: This study aimed to analyze the extent to which G. lucidum extract can reduce TNF-α and PGE2 levels in periodontitis model Sprague Dawley rats. Methods: Thirty Sprague Dawley rats were randomly divided into six groups of five rats. Periodontitis inflammation was induced by the injection of Porphyromonas gingivalis bacteria into intrasulcular gingival incisors in the lower jaw labial section. Grouping was as follows: Group K1 (healthy control); Group K2 (negative control); Group K3 (positive control with doxycycline dose 0.27 mg/kg BW); Group P1 (G. lucidum extract dose 5 mg/kg BW); Group P2 (G. lucidum extract dose 10 mg/kg BW); and Group P3 (G. lucidum extract dose 20 mg/kg BW). Samples were taken from rat gingival tissue and the levels of TNF-α and PGE2 were examined using the enzyme-linked immunosorbent assay method. Data analysis was performed using one-way analysis of variance (ANOVA) with a confidence level of 95% (p < 0.05). Results: The levels of TNF-α and PGE2 were the highest in the K2 group and the lowest in the K1 group. One-way ANOVA showed no significant difference in TNF-α and PGE2 levels between P3 and K1 group. Conclusion: G. lucidum extract can reduce TNF-α and PGE2 levels in Sprague Dawley rats with periodontitis. [ABSTRACT FROM AUTHOR]

Background: Induction of labour (IOL) is common practice and different methods carry different effectiveness and safety profiles. Objectives: To compare the effectiveness, and maternal and perinatal safety outcomes of IOL with vaginal misoprostol versus vaginal dinoprostone using individual participant data from randomised clinical trials. Search strategy: The following databases were searched from inception to March 2023: CINAHL Plus, ClinicalTrials.gov, Cochrane Pregnancy and Childbirth Group Trial Register, Ovid Embase, Ovid Emcare, Ovid MEDLINE, Scopus and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Selection criteria: Randomised controlled trials (RCTs), with viable singleton gestation, no language restrictions, and all published and unpublished data. Data collection and analysis: An individual participant data meta‐analysis was carried out. Main results: Ten of 52 eligible trials provided individual participant data, of which two were excluded after checking data integrity. The remaining eight trials compared low‐dose vaginal misoprostol versus dinoprostone, including 4180 women undergoing IOL, which represents 32.8% of all participants in the published RCTs. Of these, 2077 were assigned to low‐dose vaginal misoprostol and 2103 were assigned to vaginal dinoprostone. Compared with vaginal dinoprostone, low‐dose vaginal misoprostol had a comparable rate of vaginal birth. Composite adverse perinatal outcomes did not differ between the groups. Compared with vaginal dinoprostone, composite adverse maternal outcomes were significantly lower with low‐dose vaginal misoprostol (aOR 0.80, 95% CI 0.65–0.98, P = 0.03, I2 = 0%). Conclusions: Low‐dose vaginal misoprostol and vaginal dinoprostone for IOL are comparable in terms of effectiveness and perinatal safety. However, low‐dose vaginal misoprostol is likely to lead to a lower rate of composite adverse maternal outcomes than vaginal dinoprostone. This article includes Author Insights, a video abstract available at: https://vimeo.com/915799731. [ABSTRACT FROM AUTHOR]

Background: One in four labors are induced. The process of cervical ripening can be lengthy and pre‐labor hospitalization is required. Outpatient cervical ripening can be an attractive alternative. Objectives: To evaluate the efficacy and safety of outpatient cervical ripening with a balloon catheter compared with inpatient balloon catheter or prostaglandin E2 (PGE2). Search Strategy: The PubMed, MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases were searched from their inception to October 15, 2022. Selection Criteria: Randomized controlled trials comparing the outpatient balloon catheter with inpatient balloon catheter or inpatient PGE2 for term cervical ripening. Data Collection and Analysis: Bayesian network meta‐analysis was performed. The primary outcome was the cesarean delivery rate. The secondary outcomes included instrumental delivery, the time from intervention‐to‐birth, oxytocin augmentation, total hospital duration, and maternal/neonatal adverse events. Main Results: Twenty‐nine randomized controlled trials with a total of 6004 participants were identified. No difference in the cesarean delivery rate was revealed among the three interventions. Compared with inpatient balloon catheter, outpatient balloon catheter had shorter total hospital duration (mean difference −8.58, 95% confidence interval −17.02 to −1.10). No differences were revealed in the time from intervention‐to‐birth, instrumental delivery, postpartum hemorrhage, 5‐min Apgar score less than 7, umbilical cord arterial pH less than 7.1, and neonatal intensive care unit admission among the three interventions. Conclusions: Outpatient balloon catheter in low‐risk term pregnancies is an available option that could be considered for cervical ripening. The safety and effectiveness are comparable to inpatient cervical ripening methods. Synopsis: Outpatient balloon catheter had shorter total hospital duration compared with inpatient balloon catheter, and could be considered as an available option for cervical ripening. [ABSTRACT FROM AUTHOR]

The objective of this research was to compare the functional differences between azelaic acid and chitosan-coated azelaic acid as cosmetic raw materials in terms of skin absorption efficiency, exfoliation, anti - inflammatory and 5α-reductase inhibition. The results showed that the skin absorption of azelaic acid was significantly higher compared to azelaic-chitosan. In terms of exfoliation, both azelaic acid and azelaic-chitosan had a certain exfoliating efficacy. However, compared to azelaic-chitosan, azelaic acid alone resulted in a 25.86% higher number of detached corneocytes and a 27.80% higher total protein content. In terms of anti-inflammation, azelaicchitosan at the same concentration showed significantly greater inhibitory effects on inflammatory factors such as tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX-2) compared to decanoic acid. Besides, there was no significant difference in inhibitory activity of 5α-reductase between the two groups. These results suggested that both materials had their advantages in terms of their efficacy as cosmetic ingredients. This study contributed to harnessing the potential benefits of azelaic acid and chitosan coating as cosmetic ingredients while providing valuable reference data for evaluating the application potential of chitosan as a coating material in cosmetics. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine the differential variations in the metabolic composition of follicular fluid (FF) among normal-weight patients with polycystic ovary syndrome (PCOS) and controls and to identify potential biomarkers that may offer insights into the early identification and management of these patients. Methods: We collected FF samples from 45 normal-weight women with PCOS and 36 normal-weight controls without PCOS who were undergoing in vitro fertilization–embryo transfer. An untargeted metabolomic study of collected FF from infertile women was performed using high-performance liquid chromatography–tandem spectrometry (LC-MS). The tendency of the two groups to separate was demonstrated through multivariate analysis. Univariate analysis and variable importance in projection were used to screen out differential metabolites. Metabolic pathway analysis was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG), and a diagnostic model was established using the random forest algorithm. Results: The metabolomics analysis revealed an increase in the expression of 23 metabolites and a decrease in that of 10 metabolites in the FF of normal-weight women with PCOS. According to the KEGG pathway analysis, these differential metabolites primarily participated in the metabolism of glycerophospholipids and the biosynthesis of steroid hormones. Based on the biomarker combination of the top 10 metabolites, the area under the curve value was 0.805. The concentrations of prostaglandin E2 in the FF of individuals with PCOS exhibited an inverse association with the proportion of high-quality embryos (p < 0.05). Conclusions: Our research identified a distinct metabolic profile of the FF from normal-weight women with PCOS. The results offer a broader comprehension of the pathogenesis and advancement of PCOS, and the detected differential metabolites could be potential biomarkers and targets for the treatment of PCOS. [ABSTRACT FROM AUTHOR]

Trilobolide and its analogues belong to the guaianolide type of sesquiterpene lactones, which are characteristic and widely distributed within the families Asteraceae and Apiaceae. Certain guaianolides are receiving continuously increasing attention for their promising sarco-endoplasmic reticulum Ca2+-ATPase (SERCA)-inhibitory activity. However, because of their alkylation capabilities, they are generally toxic. Therefore, the search for compounds with significant immunobiological properties but with decreased cytotoxicities suitable for use in immune-based pharmacotherapy is ongoing. Therefore, we extended our previous investigation of the immunobiological effects of trilobolide to a series of structurally related guaianolides and germacranolides. To evaluate the relationship, we tested a series of selected derivatives containing α-methyl lactone or exomethylene lactone ring. For a wider comparison, we also included some of their glycosidic derivatives. We assessed the in vitro immunobiological effects of the tested compounds on nitric oxide (NO) production, cytokine secretion, and prostaglandin E2 (PGE2) release by mouse peritoneal cells, activated primarily by lipopolysaccharide (LPS), and evaluated their viability. The inhibitory effects of the apparently most active substance, 8-deoxylactucin, seem to be the most promising. [ABSTRACT FROM AUTHOR]

Background: The rates of labor induction and cesarean delivery is rising worldwide. With the confluence of these trends, the labor induction rate in trials of labor after cesarean can be as high as 27-32.7%. Induction of labor after one previous cesarean (IOLAC) is a high-risk procedure mainly due to the higher risk of uterine rupture. Nevertheless, the American College of Obstetricians and Gynecologists considers IOLAC as an option in motivated and informed women in the appropriate care setting. We sought to identify predictors of a composite of maternal and newborn adverse outcomes following IOLAC. Methods: The electronic medical records of women who delivered between January 2018 to September 2022 in a Malaysian university hospital were screened to identify cases of IOLAC. A case is classified as a composite adverse outcome if at least one of these 11 adverse outcomes of delivery blood loss ≥ 1000 ml, uterine scar complications, cord prolapse or presentation, placenta abruption, maternal fever (≥ 38 0C), chorioamnionitis, intensive care unit (ICU) admission, Apgar score < 7 at 5 min, umbilical artery cord artery blood pH < 7.1 or base excess ≤-12 mmol/l, and neonatal ICU admission was present. An unplanned cesarean delivery was not considered an adverse outcome as the practical management alternative for a clinically indicated IOLAC was a planned cesarean. Bivariate analysis of participants' characteristics was performed to identify predictors of their association with composite adverse outcome. Characteristics with crude p < 0.10 on bivariate analysis were incorporated into a multivariable binary logistic regression analysis model. Results: Electronic medical records of 19,064 women were screened. 819 IOLAC cases and 98 cases with composite adverse outcomes were identified. Maternal height, ethnicity, previous vaginal delivery, indication of previous cesarean, indication for IOLAC, and method of IOLAC had p < 0.10 on bivariate analysis and were incorporated into a multivariable binary logistic regression analysis. After adjustment, only maternal height and IOLAC by vaginal dinoprostone compared to Foley balloon remained significant at p < 0.05. Post hoc adjusted analysis that included all unplanned cesarean as an added qualifier for composite adverse outcome showed higher body mass index, short stature (< 157 cm), not of Chinese ethnicity, no prior vaginal delivery, prior cesarean indicated by labor dystocia, and less favorable Bishop score (< 6) were independent predictors of the expanded composite adverse outcome. Conclusion: Shorter women and IOLAC by vaginal dinoprostone compared to Foley balloon were independently predictive of composite of adverse outcome. Synopsis: Shorter stature and dinoprostone labor induction are independent predictors of a composite maternal-newborn adverse outcome excluding unplanned cesarean delivery. [ABSTRACT FROM AUTHOR]

Gastric ulceration is a common gastrointestinal ailment with serious consequences that can lead to serious illness or even death. This study aimed to examine the efficacy of tadalafil (TAD) and dexlansoprazole (DLP) in treating stomach ulcers caused by dexamethasone (DEX) in male albino Wister rats. Thirty male albino Wister rats were divided into 5 groups (6 rats each): control group received normal saline, positive control group received DEX 5 mg/kg/day intraperitoneal (i.p.) for 7 days, the third group received DLP 30 mg/kg/day orally after DEX, the fourth group received TAD 5 mg/kg/day orally after DEX, and the fifth group received DLP and TAD orally after DEX. Persistence and prevention of ulcers, pepsin activity, mucin content, and histopathological changes were evaluated after each trial. Reduced glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) levels were measured in gastric homogenates. Serum levels of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) were also measured. Treatment with either TAD or DLP alone significantly reduced ulcer index (U.I.), pepsin activity, TNF-α, IL-10 and MDA with significant rise in mucin content, PGE2, NO, GSH, and improved the histological alteration compared to DEX group. When TAD and DLP were administered together, there was a more notable decrease in U.I., pepsin activity, gastric MDA, TNF-α, and IL-10 with concomitant more significant increase in mucin content, NO content, and PGE2 production compared to the TAD or DLP groups alone. Compared to each medicine alone, TAD and DLP together have promising therapeutic potential in preventing stomach ulcers caused by DEX. [ABSTRACT FROM AUTHOR]

BackgroundLabor induction is a common obstetric intervention, increasingly performed worldwide, often using prostaglandins like misoprostol and dinoprostone.ObjectiveThis study aims to compare the effectiveness and safety of intravaginal misoprostol versus dinoprostone for inducing labor, examining their impact on various maternal and neonatal outcomes.MethodsA systematic review and meta-analysis were conducted using four databases—PubMed, Google Scholar, EBSCO, and the Cochrane Library—from January 2000 to April 2023. We included randomized controlled trials (RCTs) involving singleton pregnancies at term (37–42 weeks) with unfavorable cervices, where intravaginal misoprostol was compared to dinoprostone. Key outcomes evaluated for effectiveness included vaginal delivery within 24 h, overall vaginal delivery rate, and need for oxytocin augmentation. Safety outcomes assessed were tachysystole, uterine hyperstimulation, abnormal cardiotocography, NICU admissions, cesarean delivery, and APGAR scores. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model in Review Manager (RevMan) version 5.4.1.ResultsEight RCTs with a total of 1,801 participants (937 in the misoprostol group and 864 in the dinoprostone group) met the inclusion criteria. Misoprostol required a significantly less oxytocin augmentation than dinoprostone [RR = 0.83; 95% CI (0.71, 0.97), p = 0.02]. Other outcomes, including rates of cesarean delivery, uterine tachysystole, hyperstimulation, and NICU admissions, showed no significant differences between the two groups, indicating comparable safety and efficacy profiles.ConclusionThis meta-analysis demonstrates that intravaginal misoprostol is an effective and safe alternative to dinoprostone for labor induction at term. Misoprostol achieved comparable efficacy and safety outcomes while requiring less oxytocin augmentation, supporting its potential as a practical induction agent in clinical settings.

BackgroundEpithelial remodeling is a histopathologic feature of chronic inflammatory airway diseases including chronic rhinosinusitis (CRS). Cell-type shifts and their relationship to CRS endotypes and severity are incompletely described.ObjectiveWe sought to understand the relationship of epithelial cell remodeling to inflammatory endotypes and disease outcomes in CRS.MethodsUsing cell-type transcriptional signatures derived from epithelial single-cell sequencing, we analyzed bulk RNA-sequencing data from sinus epithelial brushings obtained from patients with CRS with and without nasal polyps in comparison to healthy controls.ResultsThe airway epithelium in nasal polyposis displayed increased tuft cell transcripts and decreased ciliated cell transcripts along with an IL-13 activation signature. In contrast, CRS without polyps showed an IL-17 activation signature. IL-13 activation scores were associated with increased tuft cell, goblet cell, and mast cell scores and decreased ciliated cell scores. Furthermore, the IL-13 score was strongly associated with a previously reported activated ("polyp") tuft cell score and a prostaglandin E2 activation signature. The Lund-Mackay score, a computed tomographic metric of sinus opacification, correlated positively with activated tuft cell, mast cell, prostaglandin E2, and IL-13 signatures and negatively with ciliated cell transcriptional signatures.ConclusionsThese results demonstrate that cell-type alterations and prostaglandin E2 stimulation are key components of IL-13-induced epithelial remodeling in nasal polyposis, whereas IL-17 signaling is more prominent in CRS without polyps, and that clinical severity correlates with the degree of IL-13-driven epithelial remodeling.

Wenjie Liu, Li Guo, Lizhen Feng, Jie Wang, Miao Zhang, Xiaobin Fan Department of Obstetrics and Gynecology, Xi’an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi’an, 710018, People’s Republic of ChinaCorrespondence: Xiaobin Fan, Email liuwj0709@163.comObjective: To evaluate factors predictive of the success of a slow-release dinoprostone vaginal insert for cervical ripening.Methods: This retrospective study included 187 women who received dinoprostone vaginal inserts for cervical ripening. The participants were divided into two groups: the transvaginal delivery group (n = 87) and cesarean section termination group (n = 100). The correlation between the parameters present before cervical ripening with dinoprostone slow release and its success, as well as complications and adverse outcomes, was analyzed. Cesarean section predictors and area under the curve (AUC) were compared between the two Groups.Results: There were statistical differences between the two groups in body mass index (BMI), height, cervical Bishop score, cephalic position, time of medication use, and fetal head position at the time of medication use (P< 0.05). The optimal thresholds for identifying cesarean section in dinoprostone vaginal insert for cervical ripening were 162.5 for height (AUC = 0.61), 10.65 cm for amniotic fluid index (AUC = 0.6), S-2.5 for cephalic position (AUC = 0.61), 5.5 for bishop score of cervix (AUC = 0.65). The height, amniotic fluid index, cephalic position, and Bishop score of the cervix were included in the same model. The AUC value of the combined model was higher than the AUC value of the single factor.Conclusion: The combined model was a better predictor of cesarean section in dinoprostone vaginal inserts for cervical ripening and labor induction. The success of cervical ripening with a dinoprostone slow-release vaginal insert can be predicted by the factors that can be recognized at admission.Keywords: dinoprostone, cervical ripening, labor induction, predictive model

Background: Primary syphilis is characterized by painless ulcerative lesions in the genitalia, the aetiology of painless remains elusive. Objectives: To investigate the role of Treponema pallidum in painless ulcer of primary syphilis, and the mechanisms underlying painless ulcers caused by T. pallidum. Methods: An experimental rabbit model of primary syphilis was established to investigate its effects on peripheral nerve tissues. Human skin fibroblasts were used to examine the role of T. pallidum in modulating neurotransmitters associated with pain and to explore the signalling pathways related to neurotransmitter secretion by T. pallidum in vitro. Results: Treponema pallidum infection did not directly lead to neuronal damage or interfere with the neuronal resting potential. Instead, it facilitated the secretion of prostaglandin E2 (PGE2) through endoplasmic reticulum stress in both rabbit and human skin fibroblasts, and upregulation of PGE2 induced the hyperpolarization of neurones. Moreover, the IRE1α/COX‐2 signalling pathway was identified as the underlying mechanism by which T. pallidum induced the production of PGE2 in human skin fibroblasts. Conclusion: Treponema pallidum promotes PGE2 secretion in skin fibroblasts, leading to the excitation of neuronal hyperpolarization and potentially contributing to the pathogenesis of painless ulcers in syphilis. [ABSTRACT FROM AUTHOR]

Background: During Treponema pallidum (T. pallidum) infection, the host's immune system actively engages in pursuit and elimination of T. pallidum, while T. pallidum skillfully employs various mechanisms to evade immune recognition. Macrophages exhibit incomplete clearance of T. pallidum in vitro and the underlying mechanism of how T. pallidum resists the attack of macrophage remains unclear. Objectives: To investigate the effect of T. pallidum membrane protein Tp47 on the phagocytosis of macrophages. Methods: THP‐1‐derived macrophages were used to investigate the role of Tp47 in the secretion of Prostaglandin E2 (PGE2) in macrophages and the mechanism by which Tp47 induced the production of PGE2, as well as the impact of PGE2 on the macrophage's phagocytosis. Results: Tp47 (1–10 μg/mL) significantly inhibited the phagocytosis of latex beads and T. pallidum in macrophages (p ≤ 0.05). PGE2 production by macrophages could be induced by Tp47, and the phagocytic function of macrophages could be restored using PGE2 antibody. Tp47 produced PGE2 by activating the PERK/NF‐κB/COX‐2 pathway in macrophages. Inhibitors targeting PERK, NF‐κB and COX‐2, respectively, reduced the level of PGE2 and restored the phagocytic function of macrophages. Conclusion: Tp47‐induced PGE2 production via the PERK/NF‐κB/COX‐2 pathway contributed to macrophage phagocytosis inhibition, which potentially contributes to immune evasion during the T. pallidum infection. [ABSTRACT FROM AUTHOR]

Background: Dinoprostone vaginal insert is the most common pharmacological method for induction of labor (IOL); however, studies on assessing the time to vaginal delivery (DT) following dinoprostone administration are limited. Aims: We sought to identify the primary factors influencing DT in women from central China, at or beyond term, who underwent IOL with dinoprostone vaginal inserts. Methods: In this retrospective observational study, we analyzed the data of 1562 women at 37 weeks 0 days to 41 weeks 6 days of gestation who underwent dinoprostone-induced labor between January 1st, 2019, and December 31st, 2021. The outcomes of interest were vaginal or cesarean delivery and factors influencing DT, including maternal complications and neonatal characteristics. Results: Among the enrolled women, 71% (1109/1562) delivered vaginally, with median DT of 740.50 min (interquartile range 443.25 to 1264.50 min). Of the remaining 29% (453/1562), who delivered by cesarean section, 11.9% (54/453) were multiparous. Multiple linear regression analysis showed that multiparity, advanced maternal age, fetal macrosomia, premature rupture of membranes (PROM), and daytime insertion of dinoprostone were the factors that significantly influenced DT. Time to vaginal delivery increased with advanced maternal age and fetal macrosomia and decreased with multiparity, PROM, and daytime insertion of dinoprostone. A mathematical model was developed to integrate these factors for predicting DT: Y = 804.478 − 125.284 × multiparity + 765.637 × advanced maternal age + 411.511 × fetal macrosomia-593.358 × daytime insertion of dinoprostone − 125.284 × PROM. Conclusions: Our findings may help obstetricians estimate the DT before placing a dinoprostone insert, which may improve patient management in busy maternity wards and minimize potential risks. [ABSTRACT FROM AUTHOR]